In "Artificial Pulmonary Surfactant", Biochimica et Biophysica Acta, 776:37-47 (1984), Shou-Hwa Yu et al. describe the natural pulmonary or lung surfactants which coat the alveoli of mammalian lungs. Such surfactants comprise lipids and surfactant-associated proteins. Pulmonary surfactant reduces surface tension at the air-liquid interface of the alveoli. Studies indicate that in the presence of surfactant, the surface tension in normally expanded lungs approximates 30 dyne/cm, while during expiration this value approaches 0 dyne/cm. Presence of pulmonary surfactant is particularly critical at birth, when the newborn infant must clear its lungs of pulmonary fluid and establish regular breathing. Absence of sufficient surfactant stores to maintain a low surface tension during the neonatal period appears to be the major factor associated with the development of the neonatal respiratory distress syndrome, also known as hyaline membrane disease, the principal cause of perinatal mortality and morbidity in developed countries. Treatment of infants suffering from advanced neonatal respiratory distress syndrome with surfactant preparations derived from bovine surfactant lipid extracts has shown a marked improvement in lung expansion and gas exchange. In like manner, a deficiency of lung surfactant in adults can cause adult respiratory distress syndrome (ARDS).
It is generally acknowledged that the ability of pulmonary surfactant to reduce the surface tension of an air/liquid interface to near 0 dyne/cm is dependent upon the formation of a monolayer of relatively pure dipalmitoyl phosphatidylcholine (DPPC) during compression. However, at normal body temperature of 37.degree. C. hydrated bilayers of DPPC exist in the gel state, from which adsorption can occur only very slowly. As a result, attempts to develop artificial mixtures which could function to transfer DPPC to the air/liquid interface at a sufficient rate to maintain normal lung functions have not been successful. One approach towards the formation of artificial surfactants has been to devise methods for dispersing DPPC using long-chain alcohols or inert hydrocarbon oils, or by administering "dry" lipid mixtures in which the DPPC is not fully hydrated.
Another possibility discussed by Yu et al., cited above, is to disperse the DPPC with other lipids which promote the formation of the hexagonal H.sub.II phase. This latter state consists of elongated cylinders of lipids in inverted micellar form with the fatty acids extending outwards and the polar head-groups binding an inner core or pore of water which extends along the elongated cylinder. Because air is more hydrophobic than water, it is postulated by Yu et al. that a cylinder of H.sub.II phase interacting with the air/liquid interface could tend to unfold, thereby transferring many lipid molecules to a surface. However, because of the thick gel-like consistency of hexagonal H.sub.II DPPC, it is not believed that DPPC in this form could be effectively administered in vivo to deposit a surfactant monolayer on alveoli surfaces.
When administering DPPC to alveoli as a lung surfactant, it is important that the DPPC form a monolayer spread over as much of the alveoli surface area as possible, to provide maximum treatment to the lung. Furthermore, the rate of monolayer deposition may be critical in the treatment of a subject with breathing difficulties brought on by respiratory distress syndrome. The prior methods for delivering DPPC to lung alveoli have not been able to deposit an effective surfactant monolayer of DPPC to the alveoli surfaces. When DPPC in bilayer form has been administered to alveoli, the spreading rate has been found to be too slow to form an effective monolayer or to provide adequate relief for breathing difficulties. Similarly, as discussed above, the thick gel-like consistency of DPPC in hexagonal H.sub.II form is believed to make it unsuitable for forming a monolayer on alveoli surfaces.